EP2454237B1 - 3-oxo-2, 3-dihydro-1h-isoindol-4-carboxamide mit selektiver parp-1-hemmung - Google Patents

3-oxo-2, 3-dihydro-1h-isoindol-4-carboxamide mit selektiver parp-1-hemmung Download PDF

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EP2454237B1
EP2454237B1 EP10728692.4A EP10728692A EP2454237B1 EP 2454237 B1 EP2454237 B1 EP 2454237B1 EP 10728692 A EP10728692 A EP 10728692A EP 2454237 B1 EP2454237 B1 EP 2454237B1
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methyl
oxo
dihydro
isoindole
carboxamide
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EP2454237A1 (de
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Gianluca Mariano Enrico Papeo
Alina Anatolievna Busel
Elena Casale
Alexander Khvat
Mikhail Yurievitch Krasavin
Paolo Orsini
Helena Posteri
Alessandra Scolaro
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Nerviano Medical Sciences SRL
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Nerviano Medical Sciences SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Claims (11)

  1. Verbindung der Formel (I)
    Figure imgb0101
     dadurch gekennzeichnet, dass
    R eine wahlweise substituierte Heterocyclyl- oder Arylgruppe ist, wobei die wahlweisen Substituenten ein oder mehrere wahlweise weiter substituierte lineare oder verzweigte C1-C6-Alkyl-, C3-C7-Cycloalkyl-, Heterocyclyl-, Aryl-, Heteroaryl-, C3-C7-Cycloalkyl-C1-C6-Alkyl-, Heterocyclyl-C1-C6-Alkyl-, Aryl-C1-C6-Alkyl- oder Heteroaryl-C1-C6-Alkylgruppe (n) oder COR4 ist und die wahlweisen weiteren Substituenten ein oder mehrere Halogen-, C1-C6-Alkyl-, Aryl- oder Heterocyclylgruppe(n), OR7, oxo (=O), SR7 oder R8O-C1-C6-Alkylgruppe sind;
    R1 und R2 unabhängig ein Wasserstoffatom oder eine lineare oder verzweigte C1-C6-Alkylgruppe sind, mit der Maßgabe, dass sie nicht beide Wasserstoffatome sind;
    R3 Wasserstoff oder ein Halogenatom ist;
    R4 OR7 ist;
    R5 und R6 unabhängig ein Wasserstoffatom oder eine wahlweise substituierte lineare oder verzweigte C1-C6-Alkyl-, C3-C7-Cycloalkyl-, C2-C6-Alkenyl-, C2-C6-Alkynyl-, Heterocyclyl-, Aryl-, Heteroaryl-, R8R9N-C1-C6-Alkyl-, R8O-C1-C6-Alkylgruppe sind oder R5 und R6 mit dem Stickstoffatom zusammengenommen, an das sie gebunden sind, eine wahlweise substituierte Heterocyclylgruppe bilden;
    R7 ein Wasserstoffatom, eine wahlweise substituierte lineare oder verzweigte C1-C6-Alkyl- oder Aryl-C1-C6-Alkylgruppe ist, wobei die Substituenten ein oder mehrere Halogenatome sind;
    R8 ein Wasserstoffatom ist;
    R9 ein Wasserstoffatom oder ein wahlweise substituiertes lineares oder verzweigtes C1-C6-Alkyl, C3-C7-Cycloalkyl, C2-C6-Alkenyl, C2-C6-Alkynyl, Heterocyclyl, Aryl, Heteroaryl, COR4 ist oder R8 und R9, mit dem Stickstoffatom zusammengenommen, an das sie gebunden sind, eine wahlweise substituierte Heterocyclylgruppe bilden, wobei R4 die obige Definition aufweist,
    oder pharmazeutisch akzeptables Salz davon.
  2. Verbindung der Formel (I) nach Anspruch 1, dadurch gekennzeichnet, dass R eine wahlweise substituierte Piperidinyl- oder Phenylgruppe ist, wobei die wahlweisen Substituenten eine oder mehrere, wahlweise weiter substituierte Methyl-, Ethyl-, Propyl-, Cyclohexyl-, Cyclopentyl-, Cyclobutyl-, Morpholinyl-, Piperazinyl-, Pyrazolyl-, Cyclohexylmethyl-, Cyclohexenylmethyl-, Piperidinylmethyl-, Benzyl-, Pyridylmethyl-, Pyrrolylmethyl-, Pyrazolylmethyl-, Imidazolylmethyl-, Thienylmethyl-, Indolylmethyl-, Thiazolylmethyl-, Furylmethylgruppe oder COR4 ist; wobei die wahlweisen weiteren Substituentem ein oder mehrere Brom-, Fluor-, Chloratome oder Isopropyl-, Methyl-, Phenyl-, Morpholinyl- oder Piperidinyl-, Hydroxymethylgruppe(n), OR7, oxo (=O) oder SR7 sind;
    R1 und R2 unabhängig ein Wasserstoffatom oder eine Methylgruppe sind, mit der Maßgabe, dass sie nicht beide Wasserstoffatome sind;
    R3 ein Wasserstoff- oder Fluoratom ist;
    R4 OR7 ist;
    R7 ein Wasserstoffatom, eine wahlweise substituierte Methyl-, tert-Butyl- oder Benzylgruppe ist, wobei die Substituenten ein oder mehrere Fluoratom(e) sind und
    R5, R6, R8 und R9 die in Anspruch 1 aufgeführte Definition aufweisen
    oder pharmazeutisch akzeptables Salz davon.
  3. Verbindung der Formel (I) nach Anspruch 1, ausgewählt aus der Gruppe bestehend aus:
    tert-Butyl-4-(4-carbamoyl-1-methyl-3-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidin-1-carboxylat,
    1-Methyl-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclohexylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    (1S)-2-(1-Cyclohexylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    (1R)-2-(1-Cyclohexylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(4,4-Difluorcyclohexyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(1H-Indol-5-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-(1-{[1-(propan-2-yl)-1H-indol-3-yl]methyl}piperidin-4-yl)-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-[1-(pyridin-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-{[4-(Benzyloxy)-1H-indol-3-yl]methyl}piperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-{1-[(4-methyl-1,3-thiazol-5-yl)methyl]piperidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(2,4-Difluorbenzyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclopentylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-{1-[(6-methylpyridin-2-yl)methyl]piperidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(Furan-2-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-{1-[3-(piperidin-1-yl)benzyl]piperidin-4-yl}-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-(1-{[6-(morpholin-4-yl)pyridin-2-yl]methyl}piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclobutylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-[1-(1H-pyrrol-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(Cyclohexylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(Cyclohex-3-en-1-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-{1-[(3-Fluorpyridin-4-yl)methyl]piperidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-{1-[(1-methyl-1H-pyrrol-2-yl)methyl]piperidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-{1-[3-(methylsulfanyl)propyl]piperidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(1H-Imidazol-2-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-{1-[(2-Chlorpyridin-3-yl)methyl]piperidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-{1-[3-(1H-pyrazol-1-yl)benzyl]piperidin-4-yl}-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-{1-[(5-methylfuran-2-yl)methyl]piperidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-{1-[(3-phenyl-1H-pyrazol-5-yl)methyl]piperidin-4-yl}-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-{1-[(5-Bromthiophen-2-yl)methyl]piperidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(3-Hydroxybenzyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-{1-[2-(Difluormethoxy)benzyl]piperidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-{[5-(Hydroxymethyl)furan-2-yl]methyl}piperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-[4-(morpholin-4-yl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-[4-(piperidin-1-yl)phenyl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-[4-(piperidin-1-ylmethyl)phenyl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    tert-Butyl 4-(4-carbamoyl-6-fluor-1-methyl-3-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidin-1-carboxylat, 6-Fluor-1-methyl-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclohexylpiperidin-4-yl)-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(4,4-Difluorcyclohexyl)piperidin-4-yl]-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid, 6-Fluor-2-[1-(1H-indol-5-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-1-methyl-3-oxo-2-[1-(pyridin-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-1-methyl-2-{1-[(4-methyl-1,3-thiazol-5-yl)methyl]piperidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(2,4-Difluorbenzyl)piperidin-4-yl]-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclopentylpiperidin-4-yl)-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-1-methyl-2-{1-[(6-methylpyridin-2-yl)methyl]piperidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-2-[1-(furan-2-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-1-methyl-3-oxo-2-{1-[3-(piperidin-1-yl)benzyl]piperidin-4-yl}-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-1-methyl-2-(1-{[6-(morpholin-4-yl)pyridin-2-yl]methyl}piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclobutylpiperidin-4-yl)-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-1-methyl-3-oxo-2-[1-(1H-pyrrol-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-1-methyl-3-oxo-2-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(Cyclohexylmethyl)piperidin-4-yl]-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(Cyclohex-3-en-1-ylmethyl)piperidin-4-yl]-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-2-{1-[(3-fluorpyridin-4-yl)methyl]piperidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-1-methyl-2-{1-[(1-methyl-1H-pyrrol-2-yl)methyl]piperidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-2-[1-(1H-imidazol-2-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-{1-[(2-Chlorpyridin-3-yl)methyl]piperidin-4-yl}-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-1-methyl-2-{1-[(5-methylfuran-2-yl)methyl]piperidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-{1-[(5-Bromthiophen-2-yl)methyl]piperidin-4-yl}-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    6-Fluor-2-(1-{[5-(hydroxymethyl)furan-2-yl]methyl}piperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    (1S)-2-(1-Cyclohexylpiperidin-4-yl)-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    (1R)-2-(1-Cyclohexylpiperidin-4-yl)-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-[4-(piperidin-4-ylmethyl)phenyl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-[4-(piperazin-1-ylmethyl)phenyl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-{4-[(1-methylpiperidin-4-yl)methyl]phenyl}-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-[3-(1-methylpiperidin-4-yl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-[3-(4-methylpiperazin-1-yl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[4-Cyclohexyl-3-(1-methylpiperidin-4-yl)phenyl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[4-Cyclohexyl-3-(4-methylpiperazin-1-yl)phenyl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid, 2-[1-(Cyclohex-3-en-1-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-[1-(2,2,2-trifluorethyl)piperidin-4-yl]-2,3-dihydro-1H-isoindol-4-carboxamidhydrat,
    1-Methyl-3-oxo-2-[1-(tetrahydrofuran-3-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    tert-Butyl-3-{[4-(4-carbamoyl-1-methyl-3-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidin-1-yl]methyl}azetidin-1- carboxylat,
    1-Methyl-2-{1-[2-methyl-2-(piperidin-1-yl)propyl]piperidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-{1-[3-(Dimethylamino)-2,2-dimethylpropyl]piperidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-{1-[(1-Ethyl-4,5-dihydro-1H-pyrazol-4-yl)methyl]piperidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-[1-(2-methylbutyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(Cyclopentylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    Methyl-4-[4-(4-carbamoyl-1-methyl-3-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidin-1-yl]butanoat,
    1-Methyl-3-oxo-2-[1-(2,2,2-trichlorethyl)piperidin-4-yl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    Ethyl-2-{[4-(4-carbamoyl-1-methyl-3-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidin-1-yl]methyl}cyclopropancarboxylat,
    2-(1-Hexylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-(1-nonylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(3-Cyclohexylpropyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-[1-(3-phenylpropyl)piperidin-4-yl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(Cyclopropylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Heptylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-(1-pentylpiperidin-4-yl)-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-[1-(2-phenylethyl)piperidin-4-yl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(3,3-Dimethylbutyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-(1-propylpiperidin-4-yl)-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(5-Hydroxypentyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-3-oxo-2-[1-(2,2,2-trifluorethyl)piperidin-4-yl]-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Butylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-[1-(2-methylpropyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-{1-[(1-methyl-1H-benzimidazol-2-yl)methyl]piperidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(2,3-Dihydroxypropyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(2,2-Dimethylpropyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(2,2-Dimethylpent-4-en-1-yl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Ethylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    1-Methyl-2-[1-(3-methylbutyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(2-Ethylbutyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclohexylpiperidin-4-yl)-1,1-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclopentylpiperidin-4-yl)-1,1-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclobutylpiperidin-4-yl)-1,1-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclohexylpiperidin-4-yl)-6-fluor-1,1-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclopentylpiperidin-4-yl)-6-fluor-1,1-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclobutylpiperidin-4-yl)-6-fluor-1,1-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2'-(1-Cyclohexylpiperidin-4-yl)-3'-oxo-2',3'-dihydrospiro[cyclopropan-1,1'-isoindol]-4'-carboxamid,
    2'-(1-Cyclohexylpiperidin-4-yl)-6'-fluor-3'-oxo-2',3'-dihydrospiro[cyclopropan-1,1'-isoindol]-4'-carboxamid,
    2'-(1-Cyclopentylpiperidin-4-yl)-3'-oxo-2',3'-dihydrospiro[cyclopropan-1,1'-isoindol]-4'-carboxamid,
    2'-(1-Cyclopentylpiperidin-4-yl)-6'-fluor-3'-oxo-2',3'-dihydrospiro[cyclopropan-1,1'-isoindol]-4'-carboxamid,
    2'-(1-Cyclobutylpiperidin-4-yl)-3'-oxo-2',3'-dihydrospiro[cyclopropan-1,1'-isoindol]-4'-carboxamid,
    2'-(1-Cyclobutylpiperidin-4-yl)-6'-fluor-3'-oxo-2',3'-dihydrospiro[cyclopropan-1,1'-isoindol]-4'-carboxamid,
    2-(1-Cyclohexylpiperidin-4-yl)-1-methyliden-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclohexylpiperidin-4-yl)-6-fluor-1-methyliden-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclopentylpiperidin-4-yl)-1-methyliden-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclopentylpiperidin-4-yl)-6-fluor-1-methyliden-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclohexylazetidin-3-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclohexylazetidin-3-yl)-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclopentylazetidin-3-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-(1-Cyclopentylazetidin-3-yl)-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid,
    2-[1-(4,4-Difluorcyclohexyl)piperidin-4-yl]-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4- carboxamid,
    2-(1-Cyclohexylpiperidin-4-yl)-6-fluor-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid und
    2-(1-Cyclohexylpiperidin-4-yl)-6-fluor-1,1-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-4-carboxamid
    oder pharmazeutisch akzeptables Salz davon.
  4. Verfahren für die Herstellung einer Verbindung der Formel (I) wie in Anspruch 1 definiert, welches Verfahren eine der folgenden Folgen von Schritten umfasst:
    FOLGE A):
    Schritt a) Halogenieren einer Verbindung der Formel (X) :
    Figure imgb0102
     wobei R1 und R3 die in Anspruch 1 aufgeführte Definition aufweisen;
    Schritt b) Cyano-deaminieren der resultierenden Verbindung der Formel (IX):
    Figure imgb0103
     wobei Hal Halogen wie Cl, Br, I ist und R1 und R3 die obige Definition aufweisen;
    Schritt c) Hydrolysieren der resultierenden Verbindung der Formel (VIII):
    Figure imgb0104
     wobei Hal, R1 und R3 die obige Definition aufweisen;
    Schritt d) Hydrolysieren der resultierenden Verbindung der Formel (VII):
    Figure imgb0105
     wobei Hal, R1 und R3 die obige Definition aufweisen;
    Schritt e) Verestern der resultierenden Verbindung der Formel (VI):
    Figure imgb0106
     wobei Hal, R1 und R3 die obige Definition aufweisen;
    Schritt f) Cyclisieren der resultierenden Verbindung der Formel (V):
    Figure imgb0107
     wobei T eine C1-C6-Alkyl- oder Aryl-C1-C6-Alkylgruppe ist; R1 und R3 die obige Definition aufweisen, mit einem geeigneten Amin der Formel (XIV):
    Figure imgb0108
     wobei R die in Anspruch 1 aufgeführte Definition aufweist;
    Schritt g) Alkylieren der resultierenden Verbindung der Formel (IV):
    Figure imgb0109
     wobei Hal, R, R1 und R3 die obige Definition aufweisen;
    Schritt h) Cyano-dehalogenieren der resultierenden Verbindung der Formel (III):
    Figure imgb0110
     wobei Hal, R, R1, R2 und R3 die obige Definition aufweisen;
    Schritt i) Hydrolysieren der resultierenden Verbindung der Formel (II):
    Figure imgb0111
     wobei R, R1, R2 und R3 die obige Definition aufweisen, um die Verbindung der Formel (I) zu ergeben:
    Figure imgb0112
     wobei R, R1, R2 und R3 die obige Definition aufweisen; oder
    FOLGE B):
    Schritt I) Halogenieren einer Verbindung der Formel (XI) :
    Figure imgb0113
     wobei R1 und R3 die obige Definition aufweisen;
    Schritt e) und m) Verestern der resultierenden Verbindung der Formel(VI) wie oben definiert und Cyano-dehalogenieren der resultierenden Verbindung der Formel (V) wie oben definiert;
    Schritt f') Cyclisieren der resultierenden Verbindung der Formel (XII):
    Figure imgb0114
     wobei T, R1 und R3 die obige Definition aufweisen, mit einem geeigneten Amin der Formel (XIV) wie oben definiert;
    Schritt g') Alkylieren der resultierenden Verbindung der Formel(XIII)
    Figure imgb0115
     wobei R, R1 und R3 die obige Definition aufweisen;
    Schritt i') Hydrolysieren der resultierenden Verbindung der Formel(XIII) wie oben definiert, um eine Verbindung der Formel (I) wie oben definiert zu ergeben, oder
    FOLGE C):
    entweder Schritt n) reduktive Aminierung einer Verbindung der Formel (XV):
    Figure imgb0116
     wobei R1 und R3 die obige Definition aufweisen;
    oder Schritt q) reduktive Alkylierung einer Verbindung der Formel (XX):
    Figure imgb0117
     wobei R1 und R3 die obige Definition aufweisen;
    Schritt o) Reagieren mit Maleinsäureanhydrid unter Diels-Alder-Bedingungen der resultierenden Verbindung der Formel (XVI)
    Figure imgb0118
     wobei R, R1, R2 und R3 die obige Definition aufweisen;
    Schritt p) Aromatisieren der resultierenden Verbindung der Formel (XVII):
    Figure imgb0119
     wobei R, R1, und R3 die obige Definition aufweisen und
    entweder Schritt i") Amidieren der resultierenden Verbindung der Formel (XVIII):
    Figure imgb0120
     wobei R, R1 und R3 die obige Definition aufweisen und R2 ein Wasserstoffatom ist, um eine Verbindung der Formel (I) wie oben definiert zu erhalten, wobei R2 ein Wasserstoffatom ist,
    oder Schritt e') Verestern einer Verbindung der Formel (XVIII) wie oben definiert, wobei R die obige Definition aufweist;
    Schritt s) N-Entschützen der resultierenden Verbindung der Formel (XXI):
    Figure imgb0121
     wobei T, R1 und R3 die obige Definition aufweisen und R die obige Definition aufweist;
    Schritt t) N-Alkylieren der resultierenden Verbindung der Formel (XXII):
    Figure imgb0122
     wobei T, R1 und R3 die obige Definition aufweisen und
    entweder Schritt r) Hydrolysieren der resultierenden Verbindung der Formel (XXI) wie oben definiert, wobei R die obige Definition aufweist;
    oder Schritt g") Alkylieren einer Verbindung der Formel (XXI) wie oben definiert, wobei R die obige Definition aufweist und
    Schritt r') Hydrolysieren der resultierenden Verbindung der Formel (XXIII):
    Figure imgb0123
     wobei T, R1 und R3 die obige Definition aufweisen
    Schritt r') Hydrolysieren der resultierenden Verbindung der Formel (XVIII), wobei R, R1 und R3 die obige Definition aufweisen und R2 kein Wasserstoffatom ist und dann Umwandeln der resultierenden Verbindung der Formel (XVIII), wobei R, R1, R2 und R3 die obige Definition aufweisen und R2 kein Wasserstoffatom ist durch Arbeiten wie oben unter Schritt i" beschrieben und nötigenfalls oder falls erwünscht Umwandeln einer Verbindung der Formel (I) in eine andere Verbindung der Formel (I) durch bekannte chemische Reaktionen; und/oder, falls erwünscht, Umwandeln einer Verbindung der Formel (I) in ein pharmazeutisch akzeptables Salz davon oder Umwandeln eines Salzes in eine freie Verbindung der Formel (I).
  5. Pharmazeutische Zusammensetzung umfassend eine therapeutisch wirksame Menge einer Verbindung der Formel (I) wie in Anspruch 1 definiert und mindestens einen pharmazeutisch akzeptablen Träger und/oder Verdünnungsmittel.
  6. Verbindung der Formel (I) wie in Anspruch 1 definiert, zur Verwendung als Medikament.
  7. Verbindung der Formel (I) wie in Anspruch 1 definiert zur Verwendung bei einem Verfahren zum Behandeln einer durch PARP-1-Proein vermittelten Krankheit.
  8. Verbindung der Formel (I) nach Anspruch 7, dadurch gekennzeichnet, dass die durch das PARP-1-Protein vermittelte, zu behandelnde Krankheit Krebs, eine kardiovaskuläre Krankheit, Verletzung oder Entzündung des Nervensystems ist.
  9. Verbindung der Formel (I) nach Anspruch 8, dadurch gekennzeichnet, dass der Krebs ein Karzinom ist wie Blasen-, Brust-, Kolon-, Nieren-, Leber-, Lungen-, einschließlich kleinzelliger Lungenkrebs, Speiseröhre-, Gallenblasen-, Eierstock-, Bauchspeicheldrüsen-, Magen-, Gebärmutterhals-, Schilddrüsen-, Prostata- und Haut- einschließlich Plattenepithelkarzinom; hämatopoetische Tumore lymphoider Abstammung einschließlich Leukämie, akuter lymphozytischer Leukämie, akuter lymphoblastischer Leukämie, B-Zellen-Lymphom, T-Zellen-Lymphom, Hodgkin-Lymphom, Nicht-Hodgkin-Lymphom, Haarzellen-Lymphom und Burkitt-Lymphom; hämatopoetische Tumore myeloischer Abstammung einschließlich akute und chronische myelogene Leukämien, myelodysplastisches Syndrom und promyelozytische Leukämie; Tumore mesenchymaler Abstammung einschließlich Fibrosarkom und Rhabdimyosarkom; Tumore des Zentral- und peripheren Nervensystems einschließlich Astrozytome, Neuroblastome, Gliome und Schwannome; andere Tumore einschließlich Melanome, Seminome, Teratokarzinome, Osteosarkome, Xeroderma pigmentosum, Keratoxanthome, Schilddrüsenfollikelkrebs und Kaposi-Sarkome.
  10. Pharmazeutische Zusammensetzung nach Anspruch 5, ferner ein oder mehrere chemotherapeutische Mittel umfassend.
  11. Produkt umfassend eine Verbindung der Formel (I) wie in Anspruch 1 definiert, oder pharmazeutische Zusammensetzung davon wie in Anspruch 5 definiert und ein oder mehrere chemotherapeutische Mittel als kombiniertes Präparat zur gleichzeitigen, getrennten oder sequentiellen Verwendung bei der Antikrebstherapie.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110218174A (zh) * 2019-07-11 2019-09-10 枣庄学院 一种化合物及其制备方法和应用

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2600867A1 (de) * 2010-08-03 2013-06-12 Nerviano Medical Sciences S.r.l. Therapeutische kombination mit einem parp-1-hemmer und einem antineoplastikum
UY33726A (es) 2010-11-15 2012-06-29 Abbott Lab Inhibidores de nampt y rock
EP2736896B1 (de) * 2011-07-26 2016-12-14 Nerviano Medical Sciences S.r.l. 3-oxo-2,3-dihydro-1h-indazole-4-carboxamide derivate als parp-1 inhibitoren
CA2855510A1 (en) * 2011-11-11 2013-05-16 Abbvie Inc. Nampt inhibitors
KR102221199B1 (ko) 2012-10-26 2021-03-04 네르비아노 메디칼 사이언시스 에스.알.엘. 선택적 ｐａｒｐ－１ 억제제로서의 ４－카복스아미도－이소인돌리논 유도체
WO2023242302A1 (en) 2022-06-15 2023-12-21 Astrazeneca Ab Combination therapy for treating cancer

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19980074060A (ko) * 1997-03-21 1998-11-05 김윤배 신규한 치환된 3,4-디알콕시페닐 유도체
US6531464B1 (en) 1999-12-07 2003-03-11 Inotek Pharmaceutical Corporation Methods for the treatment of neurodegenerative disorders using substituted phenanthridinone derivatives
WO2002068407A1 (fr) * 2001-02-28 2002-09-06 Yamanouchi Pharmaceutical Co., Ltd. Compose benzimidazole
US7232842B2 (en) 2003-01-10 2007-06-19 Board Of Trustees Of The Leland Stanford Junior University Kinase inhibitors and associated pharmaceutical compositions and methods of use
US7320992B2 (en) * 2003-08-25 2008-01-22 Amgen Inc. Substituted 2,3-dihydro-1h-isoindol-1-one derivatives and methods of use
EP1957477B1 (de) * 2005-09-29 2011-12-07 Abbott Laboratories In der 2-stellung durch phenyl substituierte 1h-benzimidazol-4-carbonsäureamide sind wirksame parp-inhibitoren
US20070161648A1 (en) 2005-10-14 2007-07-12 Hughes Terry V Substituted dihydro-isoindolones useful in treating kinase disorders
WO2007113596A1 (en) * 2006-04-03 2007-10-11 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Amide substituted indazole and benzotriazole derivatives as poly(adp-ribose)polymerase (parp) inhibitors
US8143284B2 (en) * 2006-10-05 2012-03-27 Abbott Laboratories Poly(ADP-ribose)polymerase inhibitors
WO2008154129A1 (en) * 2007-06-08 2008-12-18 Bausch & Lomb Incorporated Pharmaceutical compositions and method for treating, reducing, ameliorating, alleviating, or preventing dry eye
US8067613B2 (en) 2007-07-16 2011-11-29 Abbott Laboratories Benzimidazole poly(ADP ribose)polymerase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110218174A (zh) * 2019-07-11 2019-09-10 枣庄学院 一种化合物及其制备方法和应用

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